Project Summary Natural killer (NK) cells play an important role in the immune response to viral infection and in the eradication of stressed or transformed cells. They can also influence adaptive immune responses through production of inflammatory cytokines and modulation of dendritic cell function. Their ability to kill transformed cells and influence adaptive immunity has made them an attractive candidate for tumor immunotherapy. However, our understanding of the mechanisms controlling NK cell development and function are inadequate to allow us to predict the outcome of therapeutic manipulations on NK cell response. My research is focused on understanding the molecular mechanisms controlling innate and adaptive lymphocyte development with an emphasis on the E protein helix-loop-helix transcription factors and their antagonists that Id proteins. Id2 is critical for NK cell development but how it functions and whether it is required for proper NK cell maturation and function has remained elusive We will test the hypothesis that Id2 is required for the terminal maturation of mature (m)NK cells and therefore influences the response of NK cells to virus infection thus limiting immunologic memory in the NK cell population. We hypothesize that Id2 functions to limit E protein activity sufficiently to restrain their potential for differentiation toward alternative lymphocyte fates yet allows E proteins to activate a subset of T cell-associated signaling proteins that are required in a subset of mNK cells. We will determine the molecular mechanism by which the E proteins, which are inhibited by Id2, function to alter the fate and function of NK lineage cells. Our studies will allow us to place the functions of E proteins and Id2 into the larger network of transcriptional regulators that control NK cell development and function and will contribute to our understanding of how therapeutic interventions will influence NK cell responses.